Cancer is a major cause of death in the industrialized world for which new and more efficacious treatments are needed. Despite the existence of anti-cancer agents, there still exists a need for more effective anti-cancer agents. A promising new class of anti-cancer agents has emerged (see U.S. Pat. No. 7,550,496, incorporated herein by reference), and the most promising compound in that class, called TH-302 (see PCT Pub. Nos. WO 2007/002931; WO 2008/083101; and WO 2010/048330, each of which is incorporated herein by reference), is now in advanced clinical testing. Because of the dire prognosis for patients with cancer, further advancements in pharmaceutical management of the condition are needed.
In addition, while biological activity is a sine non qua for an effective drug, the compound must be capable of large scale manufacturing and the physical properties of the compound can markedly impact the effectiveness and cost of a formulated active ingredient. Amorphous and different crystalline solid/polymorphic forms of compounds are frequently encountered among pharmaceutically useful compounds. Polymorphism is the ability of any element or compound to crystallize as more than one distinct crystalline species. Physical properties including solubility, melting point/endotherm maximum, density, hardness, crystalline shape and stability can be quite different for different forms of the same chemical compound.
Crystalline solid and amorphous forms may be characterized by scattering techniques, e.g., x-ray diffraction powder pattern, by spectroscopic methods, e.g., infra-red, solid state 13C and 19F nuclear magnetic resonance spectroscopy and by thermal techniques, e.g, differential scanning calorimetry or differential thermal analysis. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific crystalline solid or amorphous form. Additionally, infrared, Raman and thermal methods have been used to analyze and characterize crystalline and solid amorphous forms. Solid and amorphous forms may be characterized by data from the X-ray powder diffraction pattern determined in accordance with procedures which are known in the art (see J. Haleblian, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:911-929). Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of the compounds may vary slightly, the peaks and the peak locations are characteristic for a specific crystalline solid form.
The problems which must be solved are to (i) identify a suitable manufacturing process to prepare, purify and recover the active compounds, (ii) provide an acceptable form of the compound which is soluble in pharmaceutically acceptable solvents, (iii) amenable to manipulation (e.g. flowability and particle size) and formulation with negligible decomposition or change of the physical and chemical characteristics of the compound, and (iv) exhibits acceptable chemical stability in the formulation. In addition, forms containing a high molar percent of the active ingredient are highly desirable since they minimize the quantity of material which must be formulated and administered to produce a therapeutically effective dose. These are often conflicting requirements making identification of suitable solid forms a challenging and important problem which must be solved by the skilled pharmaceutical scientist before drug development can proceed in earnest.
Therefore, there is a need for new methods of making compounds and crystalline solid forms of these compounds of the invention and an efficient process for producing the compounds and crystalline solid forms of the compounds of the invention. Solutions to the above difficulties and deficiencies are needed before compounds become effective for routine treatment of cancer.
Accordingly, efforts were made to discover other forms of compounds of the invention and to investigate the properties thereof. There were discovered crystalline solid forms of compounds of the invention. The present invention fulfills the above needs by providing polymorphs and methods for treating and preventing cancer, while presenting a better adverse effect profile.